Cutaneous malignant melanoma is the leading cause of skin cancer-related deaths. Its incidence is on the increase worldwide faster than any other cancer, with 5-year survival rates for patients with distant metastatic disease being less than 20%. Improvement of clinical outcomes for this aggressive, chemo- and radio-resistant disease remains a major clinical challenge. Significant progress in our understanding of the etiologies and genetic underpinnings of melanoma has nevertheless been made. These advances have recently led to promising results in trials of targeted therapies for this disease. The Ras/Raf/MEK/ERK pathway has been identified as the main regulator of cell proliferation in melanoma, with ERK being hyper-activated in up to 90% of human melanomas. Activating NRAS mutations are a common route to activating this pathway; mutations affecting codon 61 being the most prevalent (NRASQ61K). BRAF, one of the three human RAF genes, is also frequently mutated in melanomas, with the most common mutation being a glutamic acid for valine substitution at position 600 (V600E). BRAFV600E stimulates constitutive ERK signaling, leading to melanocyte hyper-proliferation. Early clinical experience with the novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumor response rate among patients with BRAFV600E-positive melanomas; unfortunately, patients acquire drug resistance within a few months of an initial response and combination therapies with MEK inhibitors are currently being investigated.
p53 pathway inactivation, which mainly arises as a consequence of inactivating mutations or allelic loss of the p53 gene itself, is the most common molecular defect in human cancers. Intriguingly, the p53 locus is intact in over 95% of melanoma cases, raising questions as to the pathogenic relevance of p53 in the etiology of melanoma tumor formation. At the same time, there is an increasing body of evidence supporting a relevant role for p53 in melanoma development. Loss of p53 cooperates with melanocyte-specific overexpression of activated HRASV12G and BRAFV600E in promoting melanomagenesis in mice and oncogenic NRAS cooperates with p53 loss to generate melanomas in zebrafish. Cancers that retain expression of wild-type p53 often find alternative ways to subvert p53 function, through either deregulation of upstream modulators and/or inactivation of downstream effectors. MDM2, which encodes an E3 ubiquitin ligase that controls p53 levels and function19, is amplified in human melanomas but only in 3%-5% of documented cases. Recently, MDM4 up-regulation has also been identified as a key determinant of impaired p53 function in human melanoma.
Other pathways that could become the targets of therapeutic interventions are the canonical Wnt signaling pathway and/or the transcriptional network regulated by the melanocyte lineage-specific transcription factor MITF. MITF induces gene expression patterns that prompt melanocytes to differentiate and initiate pigment production by activating genes important for melanin biosynthesis (such as Mc1r, Tyr, Dct and Trp-1) and melanosome formation (such as Pmel). Importantly, deregulation of MITF levels and/or of its transcriptional activity contributes to melanomagenesis. As such a rheostat model for MITF function was suggested in which higher expression of MITF is associated with proliferation and lower MITF levels with migration/invasion and senescence. Amplification/overexpression of MITF, found in 10%-20% of metastatic melanomas, correlates with decreased 5-year survival rates. One of the key pro-oncogenic functions of MITF relates to its ability to promote melanoma survival by promoting expression of the anti-apoptotic gene BCL-2. Wnt/β-catenin signaling directly regulates the expression of MITF and constitutive activation of Wnt/β-catenin signaling increases the proliferation of melanoma cells, accompanied by MITF-dependent increases in clonogenic growth, implicating this pathway as a promoter of melanoma progression.
Because of its ability to acquire drug resistance and chemoresistance and because melanoma is a highly dynamic and genetically heterogeneous tumor, novel treatment strategies and combination therapies are urgently needed. Several protein-coding therapeutic targets have indeed been identified for melanoma including components of the MAPkinase pathway such as BRAFV600E, MEK and a modifier of the p53 pathway, MDM4. However, the targeting of these molecules remains only applicable in a restricted number of cases (e.g., against tumors that carry the BRAFV600E mutation or overexpress MDM4 and harbor wild-type TP53).